THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation.

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus characterized by heart failure and cardiac remodeling. Previous studies show that tetrahydroberberrubine (THBru) retrogrades cardiac aging by promoting PHB2-mediated mitochondrial autophagy and prevents peritoneal adhesion by suppressing inflammation. In this study we investigated whether THBru exerted protective effect against DCM in db/db mice and potential mechanisms. Eight-week-old male db/db mice were administered THBru (25, 50 mg·kg-1·d-1, i.g.) for 12 weeks. Cardiac function was assessed using echocardiography. We showed that THBru administration significantly improved both cardiac systolic and diastolic function, as well as attenuated cardiac remodeling in db/db mice. In primary neonatal mouse cardiomyocytes (NMCMs), THBru (20, 40 µM) dose-dependently ameliorated high glucose (HG)-induced cell damage, hypertrophy, inflammatory cytokines release, and reactive oxygen species (ROS) production. Using Autodock, surface plasmon resonance (SPR) and DARTS analyses, we revealed that THBru bound to the domain of the receptor for advanced glycosylation end products (RAGE), subsequently leading to inactivation of the PI3K/AKT/NF-κB pathway. Importantly, overexpression of RAGE in NMCMs reversed HG-induced inactivation of the PI3K/AKT/NF-κB pathway and subsequently counteracted the beneficial effects mediated by THBru. We conclude that THBru acts as an inhibitor of RAGE, leading to inactivation of the PI3K/AKT/NF-κB pathway. This action effectively alleviates the inflammatory responses and oxidative stress in cardiomyocytes, ultimately leading to ameliorated DCM.

Genetic dissection of the impact of lncRNA AI662270 during the development of atherosclerosis.

BACKGROUND: Atherosclerosis is driven by synergistic interactions between pathological biomechanical and lipid metabolic factors. Long noncoding RNAs (LncRNAs) have been implicated in atherogenesis. The purpose of this study was to investigate the potential mechanism of lncRNA AI662270 on macrophage cholesterol transport in atherosclerosis. METHODS: Apolipoprotein E deficiency (ApoE-/-) mice were fed a high fat diet for 16 weeks to construct atherosclerotic model, and the mice were injected with recombinant lentivirus carrying AI662270 gene to overexpress AI662270. Macrophages were cleared by liposomal clondronate in vivo. Fundamental experiments and functional assays, hematoxylin and eosin staining, oil red O staining and others, were performed to evaluate the function of AI662270 on atherogenesis. Peritoneal macrophages were treated with oxidized low density lipoprotein (ox-LDL) to simulate in vitro model. Mechanism assays, RNA-interacting protein immunoprecipitation, RNA-protein pulldown and others, were performed to study the regulatory mechanism of AI662270 in macrophages. RESULTS: The novel AI662270 was mainly enriched in macrophages, but not in endothelial cells, smooth muscle cells and fibroblasts of mouse atherosclerotic lesions and was upregulated by ox-LDL. Overexpression of AI662270 resulted in lipid accumulation, larger atherosclerotic plaques and cardiac dysfunction in vivo. After macrophages were removed, the pro-atherogenic effect of AI662270 disappeared. Downregulation of AI662270 in macrophages protected against foam cell formation by potentiating cholesterol efflux and reducing intracellular total cholesterol. The opposite effect was observed in macrophage-specific AI662270-overexpressed cells in vitro. AI662270 bound to adenosine triphosphate-binding cassette transporter A1 (Abca1) responsible for regulating cholesterol efflux in macrophages. Forced expression of AI662270 in macrophages decreased Abca1 expression. The reverse occurred when expression of AI662270 was repressed. CONCLUSION: These findings reveal an essential role for AI662270 in atherosclerosis progression by regulating cholesterol efflux from macrophages.

Elevated Plasma Levels of Circulating Extracellular miR-320a-3p in Patients with Paroxysmal Atrial Fibrillation.

The potential of extracellular circulating microRNAs (miRNAs) as non-invasive biomarkers of atrial fibrillation (AF) has been confirmed by a number of recent studies. However, the current data for some miRNAs are controversial and inconsistent, probably due to pre-analytical and methodological differences. In this work, we attempted to fulfill the basic pre-analytical requirements provided for circulating miRNA studies for application to paroxysmal atrial fibrillation (PAF) research. We used quantitative PCR (qPCR) to determine the relative plasma levels of circulating miRNAs expressed in the heart or associated with atrial remodeling or fibrillation with reported altered plasma/serum levels in AF: miR-146a-5p, miR-150-5p, miR-19a-3p, miR-21-5p, miR-29b-3p, miR-320a-3p, miR-328-3p, miR-375-3p, and miR-409-3p. First, in a cohort of 90 adult outpatient clinic patients, we found that the plasma level of miR-320a-3p was elevated in PAF patients compared to healthy controls and hypertensive patients without AF. We further analyzed the impact of medication therapies on miRNA relative levels and found elevated miR-320a-3p levels in patients receiving angiotensin-converting-enzyme inhibitors (ACEI) therapy. Additionally, we found that miR-320a-3p, miR-21-5p, and miR-146a-5p plasma levels positively correlated with the CHA2DS2-Vasc score and were elevated in subjects with CHA2DS2-Vasc ≥ 2. Our results indicate that, amongst the analyzed miRNAs, miR-320a-3p may be considered as a potential PAF circulating plasma biomarker, leading to speculation as to whether this miRNA is a marker of platelet state change due to ACEI therapy.

The nephrotic syndrome: pathogenesis and treatment of edema formation and secondary complications.

Nephrotic syndrome is an important clinical condition affecting both children and adults. Studies suggest that the pathogenesis of edema in individual patients may occur via widely variable mechanisms, i.e., intravascular volume underfilling versus overfilling. Managing edema should therefore be directed to the underlying pathophysiology. Nephrotic syndrome is also associated with clinically important complications related to urinary loss of proteins other than albumin. This educational review focuses on the pathophysiology and management of edema and secondary complications in patients with nephrotic syndrome.

The Blood Plasma Lipidomic Profile in Atherosclerosis of the Brachiocephalic Arteries.

According to the World Health Organization, ischemic stroke is the second leading cause of death in the world. Frequently, it is caused by brachiocephalic artery (BCA) atherosclerosis. Timely detection of atherosclerosis and its unstable course can allow for a timely response to potentially dangerous changes and reduce the risk of vascular complications. Omics technologies allow us to identify new biomarkers that we can use in diagnosing diseases. This research included 90 blood plasma samples. The study group comprised 52 patients with severe atherosclerotic lesions BCA, and the control group comprised 38 patients with no BCA atherosclerosis. Targeted and panoramic lipidomic profiling of their blood plasma was carried out. There was a statistically significant difference (p < 0.05) in the values of the indices saturated fatty acids (FAs), unsaturated FAs, monounsaturated FAs, omega-3, and omega-6. Based on the results on the blood plasma lipidome, we formed models that have a fairly good ability to determine atherosclerotic lesions of the brachiocephalic arteries, as well as a model for identifying unstable atherosclerotic plaques. According only to the panoramic lipidome data, divided into groups according to stable and unstable atherosclerotic plaques, a significant difference was taken into account: p value < 0.05 and abs (fold change) > 2. Unfortunately, we did not observe significant differences according to the established plasma panoramic lipidome criteria between patients with stable and unstable plaques. Omics technologies allow us to obtain data about any changes in the body. According to our data, statistically significant differences in lipidomic profiling were obtained when comparing groups with or without BCA atherosclerosis.

Cardiac Dysfunction and Exercise Tolerance in Patients after Complex Treatment for Cranial and Craniospinal Tumors in Childhood.

State-of-the-art therapy improves the five-year survival rate of patients under the age of 20 with cranial and craniospinal tumors by up to 74%. The urgency of dealing effectively with late treatment-associated cardiovascular complications is rising. Objective: We aimed to assess echocardiographic parameters and exercise performance in subjects with a history of complex treatment for cranial and craniospinal tumors in childhood. Methods: the study of 48 subjects who underwent cranial and craniospinal irradiation for CNS tumors in childhood and 20 healthy age- and sex-matched volunteers was conducted. The examination included hormone studies, cardiopulmonary exercise testing, and, in the main group, echocardiography (ECHO). Results: In five (10.4%) patients, ECHO changes were detected after complex anti-cancer treatment: thickening and calcification of the aortic valve leaflets (2%), and reduction in the systolic LV and RV function (8% and 6%, respectively). Irradiation of various areas was a significant predictor for reduced exercise tolerance, hyperventilation at rest and upon exertion, and an increased ventilatory equivalent for carbon dioxide. Low exercise tolerance was associated with a younger age at the time of treatment initiation. Significant differences were noted between the control group and the childhood cancer survivors with endocrine disorders. Conclusions: The obtained data confirm the importance of regular cardiovascular and endocrine monitoring of this group of cancer survivors.

Tetrahydroberberrubine exhibits preventive effect on obesity by activating PGC1α-mediated thermogenesis in white and brown adipose tissue.

The escalating prevalence of obesity presents formidable challenges, necessitating the development of effective therapeutic strategies. In this study, we aimed to elucidate the preventive effects on obesity of tetrahydroberberrubine (THBru), a derivative of berberine (BBR) and to unravel its underlying mechanism. Using an obese mouse model induced by a high-fat diet (HFD), THBru was found to markedly ameliorate obesity, as evidenced by reduced body weight, decreased Lee's index, diminished fat mass in epididymal white adipose tissue (WAT) and brown adipose tissue (BAT), alongside improved dyslipidemia. Notably, at the same dose, THBru exhibited superior efficacy compared to BBR. RNA-sequencing and gene set enrichment analysis indicated THBru activated thermogenesis, which was further confirmed in WAT, BAT, and 3 T3-L1 cells. Bioinformatics analysis of RNA-sequencing data revealed the candidate gene Pgc1α, a key regulator involved in thermogenesis. Moreover, THBru was demonstrated to elevate the expression of PGC1α by stabilizing its mRNA in WAT, BAT and 3 T3-L1 cells. Furthermore, PGC1α knockdown blocked the pro-thermogenic and anti-obesity action of THBru both in vivo and in vitro. This study unravels the preventive effects of THBru on obesity through the activation of PGC1α-mediated thermogenesis, thereby delineating its potential therapeutic implications for obesity and associated disorders.

Cardiorenal syndrome: pathophysiology and treatment.

CRS is a common problem in patients with advanced heart failure. Arterial underfilling with consequent neurohormonal activation, systemic and intrarenal vasoconstriction, and salt and water retention cause the main clinical features of CRS which include a progressive decline in renal function, worsening renal function during treatment of heart failure (HF) decompensation and resistance to loop diuretics. Impaired renal function in HF patients often reflects more advanced stages of cardiac failure, and thus is associated with a worse prognosis. However, a transient fall in glomerular filtration rate may be a result of successful treatment of congestion, and thereby might not be associated with decreased survival in HF patients. This review covers basic pathophysiological mechanisms underlying the CRS and current trends in practical approaches to treat these patients.

Impact of Dapagliflozin Treatment on Serum Sodium Concentrations in Acute Heart Failure.

INTRODUCTION: The dynamics of serum sodium are important in acute heart failure (AHF), and hyponatremia is associated with a poor prognosis. The effect of sodium-glucose cotransporter type 2 inhibitors (SGLT2i) on serum sodium concentrations in AHF is unknown. METHODS: In a single-centre, controlled, randomized study, patients were prescribed dapagliflozin in addition to standard treatment during the first 24 h of hospitalization versus standard treatments. The pre-specified outcome was an absolute change in plasma sodium concentrations between randomization (first 24 h after admission) and discharge. The secondary outcomes were an absolute change in serum sodium concentrations within 48 h of randomization and the persistence of hyponatremia. RESULTS: The sample comprised 285 patients (53% males; average age 73.26 ± 13 years); 140 of these were randomized to the dapagliflozin group. The average ejection fraction was 46 ± 14%; 155 patients (54%) had ischaemic heart failure; and 35% had diabetes mellitus. Median N-terminal pro b-type natriuretic peptide was 4,225 [2,120; 9,105] pg/mL. The average estimated glomerular filtration rate was 53.9 ± 17.2 mL/min. Hospital mortality was 6.7%. At randomization, serum sodium concentrations were 139.8 ± 4.32 mmol/L in the dapagliflozin group versus 140.85 ± 4.04 mmol/L in the control group; p = 0.048. 48 h later, there was an increase in serum sodium in the dapagliflozin group (2 [-2; 4] mmol/L), as compared to the control group (-1 [-3.75; 2]); p < 0.001. This was accompanied by equilibration of the sodium levels between the groups (141.08 ± 4.08 mmol/L in the dapagliflozin group vs. 140.05 ± 4.82 mmol/L in the control group; p = 0.096). At the time of discharge, there was no difference in serum sodium concentrations (140.98 ± 4.77 mmol/L vs. 139.86 ± 4.45 mmol/L; p = 0.082). The increase in serum sodium concentrations during the period of observation [randomization; discharge] was small but statistically significant in the dapagliflozin group (1 [-3; 3.75] mmol/L vs. -2 [-4.5; 2] mmol/L; p = 0.015). Of 36 patients (21 in the dapagliflozin group and 15 in the control group) with baseline hyponatraemia, this persisted in 6 (16.6%) in the dapagliflozin group and in 11 (73.3%) in the control group (p = 0.008). CONCLUSION: The use of dapagliflozin in AHF is associated with a tendency to the increase in serum sodium concentrations and lesser persistence of hyponatremia. This effect occurred within the first 48 h and persisted until discharge. The impact of dapagliflozin on serum sodium was more pronounced in patients with hyponatremia at randomization.

Evaluation of microRNA Expression Features in Patients with Various Types of Arterial Damage: Thoracic Aortic Aneurysm and Coronary Atherosclerosis.

Circulating serum miRNA are increasingly used as biomarkers and potential treatment targets in several clinical scenarios, including cardiovascular diseases. However, the current data on circulating miRNA in thoracic aorta aneurism (TAA) patients are inconclusive. The aim of the present study is to compare the levels of several circulating miRNA in patients with degenerative TAA, coronary artery disease (CAD), and controls for special profile identification. We have identified several candidates for the role of new biomarkers: miR-143-3p, miR-181-5p, miR-126-3p, miR-126-5p, miR-145-5p, miR-150-5p, and miR-195-5p. MATERIALS AND METHODS: Serum samples of 100 patients were analyzed, including 388 TAA patients scheduled for elective surgery, 67 patients with stable CAD and 17 controls, were used for miRNA isolation and identification. RESULTS: More specific for TAA with very high predictive ability in ROC analysis was an increase in the levels of miR-21-5p, miR-29b-5p, miR-126-5p/-3p, miR-181b-5p, and miR-92a-3p, with the latter microRNA being investigated as a novel potential marker of TAA for the first time. CONCLUSION: TAA and CAD patients demonstrated a significant increase in the levels of circulating miR-126-5p/-3p, miR-181b-5p, and miR-29b-3p. More specific for TAA with very high predictive ability in ROC analysis was an increase in the levels of miR-21-5p, -29b-5p, -126-5p/-3p, 181b-5p, and -92a-3p, with the latter microRNA being investigated as a potential marker of TAA for the first time.

Cardiac Magnetic Resonance in Patients with Suspected Tachycardia-Induced Cardiomyopathy: The Impact of Late Gadolinium Enhancement and Epicardial Fat Tissue.

Tachycardia-induced cardiomyopathy (TIC) is a reversible subtype of dilated cardiomyopathy (DCM) resulting from sustained supraventricular or ventricular tachycardia and diagnosed by the normalization of left ventricular ejection fraction (LVEF) after stable sinus rhythm restoration. The aim of this study was to determine the contribution of cardiac magnetic resonance (CMR) to the differential diagnosis of TIC and DCM with persistent atrial arrythmias in patients hospitalized for the first time with heart failure (HF) with reduced LVEF of nonischemic origin. A total of 29 patients (age: 58.2 ± 16.9 years; males: 65.5%; average EF: 37.0 ± 9.5%) with persistent atrial tachyarrhythmia and first decompensation of HF without known coronary artery diseases were included in this study. The patients successfully underwent cardioversion and were observed for 30 days. The study population was divided into groups of responders (TIC patients; N = 16), which implies achieving FF > 50% or its increase > 10% in 30 days of TIC, and non-responders (N = 13). The increase in left ventricle (LV) volumes measured using CMR was significantly higher in the non-responder group when compared with the responders (114.8 mL ± 25.1 vs. 68.1 mL ± 10.5, respectively, p < 0.05). Non-responders also demonstrated decreased interventricular septum thickness (9.1 ± 0.8 vs.11.5 ± 1.3, respectively, p < 0.05). Late gadolinium enhancement (LGE) was observed in 12 patients (41.4%). The prevalence of LGE was increased in the non-responder group (25.0% vs. 65.1%, respectively, p = 0.046). Notably, a septal mid-wall LGE pattern was found exclusively in the non-responders. Epicardial adipose tissue thickness was decreased in the non-responder group versus the TIC patients. Conclusion: Patients with TIC were found to have smaller atrial and ventricular dimensions in comparison to patients with DCM. In addition, LGE was more common in DCM patients.

Personalized Medicine in Coronary Artery Disease: Where Are We in 2022?

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in developed and in most developing countries [...].

Impact of dapagliflozin treatment on renal function and diuretics use in acute heart failure: a pilot study.

OBJECTIVE: To determine the impact of sodium-dependent glucose type 2 cotransporter inhibitors on the renal function in acute heart failure. METHODS: In a single-centre, controlled, randomised study, patients were prescribed dapagliflozin in addition to standard therapy, or were in receipt of standard therapy. The prespecified outcome was renal function deterioration; the secondary outcomes were the development of resistance to diuretics, weight loss, death during hospitalisation and the rehospitalisation or death for any reason within 30 days following discharge. RESULTS: 102 patients were included (73.4±11.7 years, 57.8% men). The average left ventricular ejection fraction was 44.9%±14.7%, the average N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was 4706 (1757; 11 244) pg/mL, the average estimated glomerular filtration rate (eGFR) was 51.6±19.5 mL/min. eGFR decreased 48 hours after randomisation in the dapagliflozin group (-4.2 (-11.03; 2.28) mL/min vs 0.3 (-6; 6) mL/min; p=0.04) but did not differ between the groups on discharge (54.71±19.18 mL/min and 58.92±24.65 mL/min; p=0.36). The incidence of worsening renal function did not differ (34.4% vs 15.2%; p=0.07). In the dapagliflozin group, there was less tendency to increase the dose of loop diuretics (14% vs 30%; p=0.048), lower average doses of loop diuretics (78.46±38.95 mg/day vs 102.82±31.26 mg/day; p=0.001) and more significant weight loss (4100 (2950; 5750) g vs 3000 (1380; 4650) g; p=0.02). In-hospital mortality was 7.8% (4(8%) in the dapagliflozin and 4 (7.7%) in the control group (p=0.95). The number of deaths within 30 days following discharge in the dapagliflozin group and in the control group was 9 (19%) and 12 (25%), p=0.55; the number of rehospitalisations was 14 (29%) and 17 (35%), respectively (p=0.51). CONCLUSION: The use of dapagliflozin was associated with a more pronounced weight loss and less need to increase diuretic therapy without significant deterioration of the renal function. Dapagliflozin did not improve the in-hospital and 30-day prognosis after discharge. TRIAL REGISTRATION NUMBER: N04778787.

The Profile of Circulating Blood microRNAs in Outpatients with Vulnerable and Stable Atherosclerotic Plaques: Associations with Cardiovascular Risks.

Non-coding RNAs reflect many biological processes in the human body, including athero-sclerosis. In a cardiology outpatient department cohort (N = 83), we aimed to compare the levels of circulating microRNAs in groups with vulnerable plaques (N = 22), stable plaques (N = 23) and plaque-free (N = 17) depending on coronary computed tomography angiography and to evaluate associations of microRNA levels with calculated cardiovascular risks (CVR), based on the SCORE2 (+OP), ACC/AHA, ATP-III and MESA scales. Coronary computed tomography was performed on a 640-slice computed tomography scanner. Relative plasma levels of microRNA were assessed via a real-time polymerase chain reaction. We found significant differences in miR-143-3p levels (p = 0.0046 in plaque-free vs. vulnerable plaque groups) and miR-181b-5p (p = 0.0179 in stable vs. vulnerable plaques groups). Analysis of microRNA associations with CVR did not show significant differences for SCORE2 (+OP) and ATPIII scales. MiR-126-5p and miR-150-5p levels were significantly higher (p < 0.05) in patients with ACC/AHA risk >10% and miR-145-5p had linear relationships with ACC/AHA score (adjusted p = 0.0164). The relative plasma level of miR-195 was higher (p < 0.05) in patients with MESA risk > 7.5% and higher (p < 0.05) in patients with zero coronary calcium index (p = 0.036). A linear relationship with coronary calcium was observed for miR-126-3p (adjusted p = 0.0484). A positive correlation with high coronary calcium levels (> 100 Agatson units) was found for miR-181-5p (p = 0.036). Analyzing the biological pathways of these microRNAs, we suggest that miR-143-3p and miR-181-5p can be potential markers of the atherosclerosis process. Other miRNAs (miR-126-3p, 126-5p, 145-5p, 150-5p, 195-5p) can be considered as potential cardiovascular risk modifiers, but it is necessary to validate our results in a large prospective trial.

Scintigraphy false-positive results for cardiac amyloidosis in a patient with Danon disease.

Common diagnostic approach in patients with suspected cardiac amyloidosis includes cardiac magnetic resonance imaging and scintigraphy. We report the first clinical case of false-positive results of scintigraphy in a patient with Danon disease.

Circulating Extracellular miRNA Analysis in Patients with Stable CAD and Acute Coronary Syndromes.

Extracellular circulating microRNAs (miRNAs) are currently a focus of interest as non-invasive biomarkers of cardiovascular pathologies, including coronary artery disease (CAD) and acute coronary syndromes (ACS): myocardial infarction with and without ST-segment elevation (STEMI and NSTEMI) and unstable angina (UA). However, the current data for some miRNAs are controversial and inconsistent, probably due to pre-analytical and methodological variances in different studies. In this work, we fulfilled the basic pre-analytical requirements provided for circulating miRNA studies for application to stable CAD and ACS research. We used quantitative PCR to determine the relative plasma levels of eight circulating miRNAs that are potentially associated with atherosclerosis. In a cohort of 136 adult clinic CAD patients and outpatient controls, we found that the plasma levels of miR-21-5p and miR-146a-5p were significantly elevated in ACS patients, and the level of miR-17-5p was decreased in ACS and stable CAD patients compared to both healthy controls and hypertensive patients without CAD. Within the ACS patient group, no differences were found in the plasma levels of these miRNAs between patients with positive and negative troponin, nor were any differences found between STEMI and NSTEMI. Our results indicate that increased plasma levels of miR-146a-5p and miR-21-5p can be considered general ACS circulating biomarkers and that lowered miR-17-5p can be considered a general biomarker of CAD.

Noninvasive Assessment of the Fractional Flow Reserve with the CT FFRc 1D Method: Final Results of a Pilot Study.

Background: Until recently, Russia did not utilize noninvasive fractional flow reserve (FFR) assessment. We developed an automated algorithm for noninvasive assessment of FFR based on a one-dimensional (1D) mathematical modeling. Objective: The research aims to evaluate the diagnostic accuracy of this algorithm. Methods: The study enrolled 80 patients: 16 of them underwent 64-slice computed tomography - included retrospectively, 64 - prospectively, with a 640-slice CT scan. Specialists processed CT images and evaluated noninvasive FFR. Ischemia was confirmed if FFR < 0.80 and disproved if FFR ≥ 0.80. The prospective group of patients was hospitalized for invasive FFR assessment as a reference standard. If ischemic, patients underwent stent implantation. In the retrospective group, patients already had invasive FFR values.Statistical analysis was performed using GraphPad Prism 8. We compared two methods using a Bland-Altman plot and per-vessel ROC curve analysis. Considering the abnormality of distribution by the Kolmogorov-Smirnov test, we have used Spearman's rank correlation coefficient. Results: During data processing, three patients of the retrospective and 46 patients of the prospective group were excluded. The sensitivity of our method was 66.67% (95% CI: 46.71-82.03); the specificity was 78.95% (95% CI: 56.67-91.49), p = 0.0052, in the per-vessel analysis. In per-patient analysis, the sensitivity was 69.57% (95% CI: 49.13-84.40); the specificity was 87.50% (95% CI: 52.91-99.36), p = 0.0109. The area under the ROC curve in the per-vessel analysis was 77.52% (95% CI: 66.97-88.08), p < 0.0001. Conclusion: The obtained indices of sensitivity, specificity, PPV, and NPV are, in general, comparable to those in other studies. Moreover, the noninvasive values of FFR yielded a high correlation coefficient with the invasive values. However, the AUC was not high enough, 77.52 (95% CI: 66.97-88.08), p < 0.0001. The discrepancy is probably attributed to the initial data heterogeneity and low statistical power.

Rationale and Design of the Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure Study.

AIMS: Although acute heart failure (AHF) with volume overload is treated with loop diuretics, their dosing and type of administration are mainly based upon expert opinion. A recent position paper from the Heart Failure Association (HFA) proposed a step-wise pharmacologic diuretic strategy to increase the diuretic response and to achieve rapid decongestion. However, no study has evaluated this protocol prospectively. METHODS AND RESULTS: The Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure (ENACT-HF) study is an international, multicentre, non-randomized, open-label, pragmatic study in AHF patients on chronic loop diuretic therapy, admitted to the hospital for intravenous loop diuretic therapy, aiming to enrol 500 patients. Inclusion criteria are as follows: at least one sign of volume overload (oedema, ascites, or pleural effusion), use ≥ 40 mg of furosemide or equivalent for >1 month, and a BNP > 250 ng/L or an N-terminal pro-B-type natriuretic peptide > 1000 pg/L. The study is designed in two sequential phases. During Phase 1, all centres will treat consecutive patients according to the local standard of care. In the Phase 2 of the study, all centres will implement a standardized diuretic protocol in the next cohort of consecutive patients. The protocol is based upon the recently published HFA algorithm on diuretic use and starts with intravenous administration of two times the oral home dose. It includes early assessment of diuretic response with a spot urinary sodium measurement after 2 h and urine output after 6 h. Diuretics will be tailored further based upon these measurements. The study is powered for its primary endpoint of natriuresis after 1 day and will be able to detect a 15% difference with 80% power. Secondary endpoints are natriuresis and diuresis after 2 days, change in congestion score, change in weight, in-hospital mortality, and length of hospitalization. CONCLUSIONS: The ENACT-HF study will investigate whether a step-wise diuretic approach, based upon early assessment of urinary sodium and urine output as proposed by the HFA, is feasible and able to improve decongestion in AHF with volume overload.

Evaluation of discriminative capacity of two formulas of CKD-EPI to predict complications after the first episode of heart failure with preserved ejection fraction.

Background: Determining the prognosis of heart failure with preserved ejection fraction (HFpEF) is problematic, as the ejection fraction cannot be used. Formulae that estimate glomerular filtration rate (eGFR) may be potential prognosticators for this condition, since renal dysfunction is a well-known predictor of poor outcomes of all forms of heart failure. Methods: A prospective observational study of 117 HFpEF patients (average age 71.6±9.1 years; 65.8% women) who had eGFR determined after their first episode of cardiac decompensation by two different chronic kidney disease epidemiology collaboration (CKD-EPI) equations. The ability to predict hospitalizations and mortality over 24 months by the two equations were compared. Results: The CKD-EPI formula based on serum creatinine only performed poorly. However, the CKD-EPI equation that used both serum creatinine and serum cystatin C was associated with unfavorable outcome: eGFR <45 mL/min/1.73 m2 predicted 24-month mortality (HR=4.21 [1.32;13.43], p=0.02) and the combined endpoint of mortality and hospitalization (HR 2.45 [1.42;4.22], p=0.001). . Conclusions: eGFR by the CKD-EPI equation based on serum creatinine and cystatin C levels, but not by the CKD-EPI creatinine only equation, predicts the outcome of HFpEF patients.

Low aquaporin-2 excretion in the nephrotic syndrome: an escape from the vasopressin regulating effect.

PURPOSE: Experimental studies suggest that the nephrotic syndrome is associated with "vasopressin escape", characterized by low aquaporin-2 (AQP2) expression in the collecting duct despite high vasopressin secretion. We investigated this phenomenon in patients with the nephrotic syndrome. PATIENTS AND METHODS: We recruited 47 patients with proteinuric kidney disease who were distributed into the following four groups: 1) nephrotic syndrome with kidney dysfunction (n=10); 2) nephrotic syndrome with normal kidney function (n=16); 3) partial remission of nephrotic syndrome (n=10); and 4) minimal proteinuria (n=11). Nine healthy volunteers comprised a control group. Serum copeptin level (as a marker of vasopressin secretion) and urinary AQP2 were measured using ELISA. RESULTS: Nephrotic syndrome was associated with a significant increase in serum copeptin levels compared with those in the other groups (all P<0.05). In patients with nephrotic syndrome and a partial remission of nephrotic syndrome combined, there was more than a ten-fold decrease in the median urinary AQP2 excretion (0.03 ng/mL) compared with healthy volunteers (0.41 ng/mL; P<0.001) and more than a five-fold decrease compared with patients with minimal proteinuria (0.21 ng/mL; P<0.05). Unlike copeptin levels, the median urinary AQP2 excretion in patients with minimal proteinuria also decreased but less significantly than in those with nephrotic syndrome. There was a negative correlation between the urinary AQP2 excretion and daily proteinuria (R=-0.41; P=0.005). CONCLUSION: Our clinical study was the first to demonstrate low AQP2 excretion in nephrotic syndrome that may indicate an escape from the vasopressin regulating effect.